Synergistic Antiproliferative Effects of Combined γ -Tocotrienol and PPAR γ Antagonist Treatment Are Mediated through PPAR γ -Independent Mechanisms in Breast Cancer Cells.

Abhita Malaviya,Paul W Sylvester

doi:10.1155/2014/439146

Abstract

Previous findings showed that the anticancer effects of combined γ-tocotrienol and peroxisome proliferator activated receptor γ (PPARγ) antagonist treatment caused a large reduction in PPARγ expression. However, other studies suggest that the antiproliferative effects of γ-tocotrienol and/or PPARγ antagonists are mediated, at least in part, through PPARγ-independent mechanism(s). Studies were conducted to characterize the role of PPARγ in mediating the effects of combined treatment of γ-tocotrienol with PPARγ agonists or antagonists on the growth of PPARγ negative +SA mammary cells and PPARγ-positive and PPARγ-silenced MCF-7 and MDA-MB-231 breast cancer cells. Combined treatment of γ-tocotrienol with PPARγ antagonist decreased, while combined treatment of γ-tocotrienol with PPARγ agonist increased, growth of all cancer cells. However, treatment with high doses of 15d-PGJ2, an endogenous natural ligand for PPARγ, had no effect on cancer cell growth. Western blot and qRT-PCR studies showed that the growth inhibitory effects of combined γ-tocotrienol and PPARγ antagonist treatment decreased cyclooxygenase (COX-2), prostaglandin synthase (PGDS), and prostaglandin D2 (PGD2) synthesis. In conclusion, the anticancer effects of combined γ-tocotrienol and PPARγ antagonists treatment in PPARγ negative/silenced breast cancer cells are mediated through PPARγ-independent mechanisms that are associated with a downregulation in COX-2, PGDS, and PGD2 synthesis.

Highlights

Introduction γTocotrienol is a member of the vitamin E family that displays potent anticancer activity at treatment doses that have little or no effect on normal cell function and viability [1,2,3,4]
Results from the present study demonstrate that the effects resulting from combined treatment of γ-tocotrienol with peroxisome proliferator activated receptor γ (PPARγ) agonist or antagonist are mediated through PPARγindependent mechanism(s)
This suggestion is supported by the findings that the anticancer effects of combined treatment of γ-tocotrienol with PPARγ antagonists are observed in PPARγ-negative +SA mammary tumor cells, as well as PPARγ silenced PPARγ positive MCF-7 and MDA-MB-231 breast cancer cells

Summary

Introduction

Introduction γTocotrienol is a member of the vitamin E family that displays potent anticancer activity at treatment doses that have little or no effect on normal cell function and viability [1,2,3,4]. Combined treatment of γ-tocotrienol with the PPARγ antagonists, GW9662 and T0070907, significantly inhibited growth of MCF-7 and MDA-MB-231 breast cancer cells, and this effect was associated with a corresponding decrease in PPARγ activity and expression. Combined treatment of γ-tocotrienol with the PPARγ agonists, rosiglitazone and troglitazone, was found to stimulate tumor cell growth, and this effect was associated with an increase in PPARγ activity and expression [9]. While these findings suggest that treatments that reduce PPARγ activity suppress, whereas treatments that increase PPARγ activity, enhance breast cancer cell growth, the possibility exists that these effects are mediated, at least in part, through PPARγ-independent mechanism(s)

Methods

Results

Discussion

Conclusion